Islet transplantation is currently being explored as a treatment for patients with type 1 diabetes. A hallmark in the "Edmonton protocol" is repeated infusions of islets obtained from 2-4 donors. In order to establish islet transplantation as an accepted treatment modality, and make tolerance induction regimes applicable, it is essential that the donor: recipient ratio is brought down to 1:1. A conceivable strategy to achieve this goal is presented. The Nordic Network for clinical islet transplantation serves a population of 25 million people and involves eight participating transplant centers. Islet isolation is centralized and over 400 human pancreases have been processed. Quality control criteria for release of human islets for clinical transplantation have been defined. Each participating transplant center will annually transplant 5-10 patients, establishing the program as one of the largest in the world (in total 35-70 patients/year). The size of the program and the uniformity of all the steps involved, from organ retrieval and islet isolation to clinical transplantation and post operative management, will make it possible to perform well controlled clinical studies within the network. We have in a series of reports demonstrated that an adverse thrombotic and inflammatory reaction (IBMIR) is elicited when islets come in contact with ABO compatible blood: characterized by a rapid binding, and activation of platelets to the islet surface and activation of the coagulation and complement systems. Within 15 minutes leukocytes are found infiltrating the islets resulting in disruption of islet integrity and islet loss. The mechanisms triggering IBMIR in clinical islet transplantation have been defined and clinically applicable inhibitors identified. The application builds on the notion that IBMIR is induced as a consequence of the interplay between the transplanted islets and the innate immune system of the recipient. This intense inflammatory response is the result of a chain of events which is already induced in the islets of the donor and aggravated by handling of the pancreas from retrieval until the isolated islets successfully engraft in the recipient. The experimental studies proposed aim to develop novel techniques and agents to down-regulate the inflammatory response in isolated islets and to minimize the innate immune response in the recipient. The present proposal aims to translate these findings to clinical islet transplantation making it possible to stepwise develop a clinical applicable protocol enabling "cure" of patients with type 1 diabetes with islets from only one human pancreas, retrieved from a donor fulfilling the standard criteria for kidney donation. The successful completion of the clinical studies proposed will form a foundation for subsequent clinical trials aiming for induction of immunological tolerance.